Phencyclidine (PCP) and sigma receptors, though linked in terms of their historical development, and their generally high affinity interactions with (+)-opiates, are now known to be pharmacologically and biochemically distinct binding sites. The PCP binding site, because it is but one component of the NMDA receptor, is relevant to drug abuse research because the NMDA receptor plays important roles in neuronal processes involved in substance abuse, such as memory, propagation of seizures and kindling, tolerance and dependence. Previous studies showed that the PCP analog, [3H]TCP labels two high affinity PCP binding sites: PCP site 1 (NMDA-receptor-associated) and PCP site 2 (biogenic-amine -transporter-associated). Collaborative investigations with F. Ivy Carroll lead to the discovery of RTI-4793-14 and RTI-4793-41, which have high potency and selectivity for PCP site 2. This novel pyrole has a neurochemical profile consistent with that of an antidepressant. Behavioral studies show that selected PCP site 2 ligands show promise as potential anti-craving medications.